CoChat
Sign Up
Cited by 72Hair Growth and DisordersWnt/β-catenin signaling in development and cancerCancer and Skin Lesions

Compartmentalized Epidermal Activation of β-Catenin Differentially Affects Lineage Reprogramming and Underlies Tumor Heterogeneity

Open access
Kretzschmar, Kai, Weber, Christine, Driskell, Ryan R., Calonje, Eduardo, Watt, Fiona M.·2016·Cell Reports
DOI 10.1016/j.celrep.2015.12.041PMC PMC4713864
Open this paper in CoChat — free accountOpen PDF

Abstract

Wnt/β-catenin activation in adult epidermis can induce new hair follicle formation and tumor development. We used lineage tracing to uncover the relative contribution of different stem cell populations. LGR6(+) and LRIG1(+) stem cells contributed to ectopic hair follicles formed in the sebaceous gland upon β-catenin activation, whereas LGR5(+) cells did not. Lgr6, but not Lrig1 or Lgr5, was expressed in a subpopulation of interfollicular epidermal cells that were competent to form new hair follicles. Oncogenic β-catenin expression in LGR5(+) cells led to formation of pilomatricomas, while LRIG1(+) cells formed trichoadenomas and LGR6(+) cells formed dermatofibromas. Tumor formation was always accompanied by a local increase in dermal fibroblast density and transient extracellular matrix remodeling. However, each tumor had a distinct stromal signature in terms of immune cell infiltrate and expression of CD26 and CD44. We conclude that compartmentalization of epidermal stem cells underlies different responses to β-catenin and skin tumor heterogeneity.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2015.12.041

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The gradual nature of transitions observed has given rise to the view that the majority of stromal fibroblasts initially originate from local fibroblasts that experience some form of tissue dysfunction.

    “The gradual nature of the transitions observed has given rise to the view that the majority of stromal fibroblasts initially originate from local fibroblasts that experience some form of tissue dysfunction31,32.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [31]

    The Discussion (page not supplied) reports a local increase in fibroblast density and transient extracellular-matrix remodeling after epidermal β-catenin activation. It does not say that most stromal fibroblasts originate from local fibroblasts experiencing tissue dysfunction, or link that view to gradual transitions. Searches for fibroblast origin and recruitment found no passage addressing those points. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 65

  1. Arwert E.N. Lal R. Quist S. Rosewell I. van Rooijen N. Watt F.M. Tumor formation initiated by nondividing epidermal cells via an inflammatory infiltrate Proc. Natl. Acad. Sci. USA 107 2010 19903 19908 21041641 PMC2993377
  2. Arwert E.N. Hoste E. Watt F.M. Epithelial stem cells, wound healing and cancer Nat. Rev. Cancer 12 2012 170 180 22362215
  3. Arwert E.N. Mentink R.A. Driskell R.R. Hoste E. Goldie S.J. Quist S. Watt F.M. Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation Oncogene 31 2012 992 1000 21765471
  4. Baker C.M. Verstuyf A. Jensen K.B. Watt F.M. Differential sensitivity of epidermal cell subpopulations to beta-catenin-induced ectopic hair follicle formation Dev. Biol. 343 2010 40 50 20398648 PMC3098388
  5. Barker N. van Es J.H. Kuipers J. Kujala P. van den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5 Nature 449 2007 1003 1007 17934449
  6. Barker N. Ridgway R.A. van Es J.H. van de Wetering M. Begthel H. van den Born M. Danenberg E. Clarke A.R. Sansom O.J. Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer Nature 457 2009 608 611 19092804
  7. Beronja S. Janki P. Heller E. Lien W.H. Keyes B.E. Oshimori N. Fuchs E. RNAi screens in mice identify physiological regulators of oncogenic growth Nature 501 2013 185 190 23945586 PMC3774280
  8. Blanpain C. Lowry W.E. Geoghegan A. Polak L. Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche Cell 118 2004 635 648 15339667
  9. Blanpain C. Horsley V. Fuchs E. Epithelial stem cells: turning over new leaves Cell 128 2007 445 458 17289566 PMC2408375
  10. Braun K.M. Niemann C. Jensen U.B. Sundberg J.P. Silva-Vargas V. Watt F.M. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis Development 130 2003 5241 5255 12954714
  11. Brownell I. Guevara E. Bai C.B. Loomis C.A. Joyner A.L. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells Cell Stem Cell 8 2011 552 565 21549329 PMC3089905
  12. Calonje E. Dermatofibroma (fibrous histiocytoma): an inflammatory or neoplastic disorder? Histopathology 39 2001 213 11493340
  13. Chen T.C. Kuo T. Chan H.L. Dermatofibroma is a clonal proliferative disease J. Cutan. Pathol. 27 2000 36 39 10660130
  14. Chiang M.F. Yang S.Y. Lin I.Y. Hong J.B. Lin S.J. Ying H.Y. Chen C.M. Wu S.Y. Liu F.T. Lin K.I. Inducible deletion of the Blimp-1 gene in adult epidermis causes granulocyte-dominated chronic skin inflammation in mice Proc. Natl. Acad. Sci. USA 110 2013 6476 6481 23576729 PMC3631680
  15. Choi Y.S. Zhang Y. Xu M. Yang Y. Ito M. Peng T. Cui Z. Nagy A. Hadjantonakis A.K. Lang R.A. Distinct functions for Wnt/β-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis Cell Stem Cell 13 2013 720 733 24315444 PMC3900235
  16. Collins C.A. Kretzschmar K. Watt F.M. Reprogramming adult dermis to a neonatal state through epidermal activation of β-catenin Development 138 2011 5189 5199 22031549 PMC3210498
  17. Deschene E.R. Myung P. Rompolas P. Zito G. Sun T.Y. Taketo M.M. Saotome I. Greco V. β-Catenin activation regulates tissue growth non-cell autonomously in the hair stem cell niche Science 343 2014 1353 1356 24653033 PMC4096864
  18. Donati G. Proserpio V. Lichtenberger B.M. Natsuga K. Sinclair R. Fujiwara H. Watt F.M. Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors Proc. Natl. Acad. Sci. USA 111 2014 E1501 E1509 24706781 PMC3992657
  19. Driskell R.R. Lichtenberger B.M. Hoste E. Kretzschmar K. Simons B.D. Charalambous M. Ferron S.R. Herault Y. Pavlovic G. Ferguson-Smith A.C. Watt F.M. Distinct fibroblast lineages determine dermal architecture in skin development and repair Nature 504 2013 277 281 24336287 PMC3868929
  20. Edward M. Gillan C. Micha D. Tammi R.H. Tumour regulation of fibroblast hyaluronan expression: a mechanism to facilitate tumour growth and invasion Carcinogenesis 26 2005 1215 1223 15746159
  21. Füllgrabe A. Joost S. Are A. Jacob T. Sivan U. Haegebarth A. Linnarsson S. Simons B.D. Clevers H. Toftgård R. Kasper M. Dynamics of Lgr6+ progenitor cells in the hair follicle, sebaceous gland, and interfollicular epidermis Stem Cell Reports 5 2015 843 855 PMC4649262 26607954
  22. Gat U. DasGupta R. Degenstein L. Fuchs E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin Cell 95 1998 605 614 9845363
  23. Gomez C. Chua W. Miremadi A. Quist S. Headon D.J. Watt F.M. The interfollicular epidermis of adult mouse tail comprises two distinct cell lineages that are differentially regulated by Wnt, Edaradd, and Lrig1 Stem Cell Reports 1 2013 19 27 24052938 PMC3757744
  24. Grachtchouk M. Pero J. Yang S.H. Ermilov A.N. Michael L.E. Wang A. Wilbert D. Patel R.M. Ferris J. Diener J. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations J. Clin. Invest. 121 2011 1768 1781 21519145 PMC3083781
  25. Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation Cell 144 2011 646 674 21376230
  26. Harada N. Tamai Y. Ishikawa T. Sauer B. Takaku K. Oshima M. Taketo M.M. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene EMBO J. 18 1999 5931 5942 10545105 PMC1171659
  27. Huelsken J. Vogel R. Erdmann B. Cotsarelis G. Birchmeier W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin Cell 105 2001 533 545 11371349
  28. Jaks V. Barker N. Kasper M. van Es J.H. Snippert H.J. Clevers H. Toftgård R. Lgr5 marks cycling, yet long-lived, hair follicle stem cells Nat. Genet. 40 2008 1291 1299 18849992
  29. Jensen K.B. Collins C.A. Nascimento E. Tan D.W. Frye M. Itami S. Watt F.M. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis Cell Stem Cell 4 2009 427 439 19427292 PMC2698066
  30. Karin M. NF-kappaB as a critical link between inflammation and cancer Cold Spring Harb. Perspect. Biol. 1 2009 a000141 20066113 PMC2773649
  31. Klaus A. Birchmeier W. Wnt signalling and its impact on development and cancer Nat. Rev. Cancer 8 2008 387 398 18432252
  32. Kretzschmar K. Watt F.M. Lineage tracing Cell 148 2012 33 45 22265400
  33. Kretzschmar K. Watt F.M. Markers of epidermal stem cell subpopulations in adult mammalian skin Cold Spring Harb. Perspect. Med. 4 2014 a013631 24993676 PMC4200210
  34. Kretzschmar K. Cottle D.L. Schweiger P.J. Watt F.M. The androgen receptor antagonizes Wnt/β-catenin signaling in epidermal stem cells J. Invest. Dermatol. 135 2015 2753 2763 26121213 PMC4641324
  35. Kurokawa I. Mizutani H. Nishijima S. Kato N. Yasui K. Tsubura A. Trichoadenoma: cytokeratin expression suggesting differentiation towards the follicular infundibulum and follicular bulge regions Br. J. Dermatol. 153 2005 1084 1086 16225641
  36. Leibl H. Hutterer J. Korschan H. Schuler G. Tani M. Tschachler E. Romani N. Wolff K. Stingl G. Expression of the Ly-5 alloantigenic system on epidermal cells J. Invest. Dermatol. 84 1985 91 95 2857189
  37. Liao X.H. Nguyen H. Epidermal expression of Lgr6 is dependent on nerve endings and Schwann cells Exp. Dermatol. 23 2014 195 198 24499442 PMC4089962
  38. Lim X. Nusse R. Wnt signaling in skin development, homeostasis, and disease Cold Spring Harb. Perspect. Biol. 5 2013 a008029 23209129 PMC3552514
  39. Lim X. Tan S.H. Koh W.L. Chau R.M. Yan K.S. Kuo C.J. van Amerongen R. Klein A.M. Nusse R. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling Science 342 2013 1226 1230 24311688 PMC4081860
  40. Lowry W.E. Blanpain C. Nowak J.A. Guasch G. Lewis L. Fuchs E. Defining the impact of beta-catenin/Tcf transactivation on epithelial stem cells Genes Dev. 19 2005 1596 1611 15961525 PMC1172065
  41. Madisen L. Zwingman T.A. Sunkin S.M. Oh S.W. Zariwala H.A. Gu H. Ng L.L. Palmiter R.D. Hawrylycz M.J. Jones A.R. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain Nat. Neurosci. 13 2010 133 140 20023653 PMC2840225
  42. Malanchi I. Peinado H. Kassen D. Hussenet T. Metzger D. Chambon P. Huber M. Hohl D. Cano A. Birchmeier W. Huelsken J. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling Nature 452 2008 650 653 18385740
  43. Means A.L. Xu Y. Zhao A. Ray K.C. Gu G. A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs Genesis 46 2008 318 323 18543299 PMC3735352
  44. Merrill B.J. Gat U. DasGupta R. Fuchs E. Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin Genes Dev. 15 2001 1688 1705 11445543 PMC312726
  45. Morimoto C. Schlossman S.F. The structure and function of CD26 in the T-cell immune response Immunol. Rev. 161 1998 55 70 9553764
  46. Müller-Röver S. Handjiski B. van der Veen C. Eichmüller S. Foitzik K. McKay I.A. Stenn K.S. Paus R. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages J. Invest. Dermatol. 117 2001 3 15 11442744
  47. Niemann C. Owens D.M. Hülsken J. Birchmeier W. Watt F.M. Expression of DeltaNLef1 in mouse epidermis results in differentiation of hair follicles into squamous epidermal cysts and formation of skin tumours Development 129 2002 95 109 11782404
  48. Niemann C. Owens D.M. Schettina P. Watt F.M. Dual role of inactivating Lef1 mutations in epidermis: tumor promotion and specification of tumor type Cancer Res. 67 2007 2916 2921 17409394
  49. Nijhof J.G. Braun K.M. Giangreco A. van Pelt C. Kawamoto H. Boyd R.L. Willemze R. Mullenders L.H. Watt F.M. de Gruijl F.R. van Ewijk W. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells Development 133 2006 3027 3037 16818453
  50. Page M.E. Lombard P. Ng F. Göttgens B. Jensen K.B. The epidermis comprises autonomous compartments maintained by distinct stem cell populations Cell Stem Cell 13 2013 471 482 23954751 PMC3793873
  51. Pálmer H.G. Anjos-Afonso F. Carmeliet G. Takeda H. Watt F.M. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis PLoS ONE 3 2008 e1483 18213391 PMC2198947
  52. Peterson S.C. Eberl M. Vagnozzi A.N. Belkadi A. Veniaminova N.A. Verhaegen M.E. Bichakjian C.K. Ward N.L. Dlugosz A.A. Wong S.Y. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches Cell Stem Cell 16 2015 400 412 25842978 PMC4387376
  53. Powell A.E. Wang Y. Li Y. Poulin E.J. Means A.L. Washington M.K. Higginbotham J.N. Juchheim A. Prasad N. Levy S.E. The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor Cell 149 2012 146 158 22464327 PMC3563328
  54. Shimanovich I. Krahl D. Rose C. Trichoadenoma of Nikolowski is a distinct neoplasm within the spectrum of follicular tumors J. Am. Acad. Dermatol. 62 2010 277 283 20115950
  55. Silva-Vargas V. Lo Celso C. Giangreco A. Ofstad T. Prowse D.M. Braun K.M. Watt F.M. Beta-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells Dev. Cell 9 2005 121 131 15992546
  56. Snippert H.J. Haegebarth A. Kasper M. Jaks V. van Es J.H. Barker N. van de Wetering M. van den Born M. Begthel H. Vries R.G. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin Science 327 2010 1385 1389 20223988
  57. Solanas G. Benitah S.A. Regenerating the skin: a task for the heterogeneous stem cell pool and surrounding niche Nat. Rev. Mol. Cell Biol. 14 2013 737 748 24064540
  58. Takeda H. Lyle S. Lazar A.J.F. Zouboulis C.C. Smyth I. Watt F.M. Human sebaceous tumors harbor inactivating mutations in LEF1 Nat. Med. 12 2006 395 397 16565724
  59. Watt F.M. Collins C.A. Role of beta-catenin in epidermal stem cell expansion, lineage selection, and cancer Cold Spring Harb. Symp. Quant. Biol. 73 2008 503 512 19022747
  60. Watt F.M. Jensen K.B. Epidermal stem cell diversity and quiescence EMBO Mol. Med. 1 2009 260 267 20049729 PMC2850061
  61. Wielenga V.J. Smits R. Korinek V. Smit L. Kielman M. Fodde R. Clevers H. Pals S.T. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway Am. J. Pathol. 154 1999 515 523 10027409 PMC1850011
  62. Wong V.W. Stange D.E. Page M.E. Buczacki S. Wabik A. Itami S. van de Wetering M. Poulsom R. Wright N.A. Trotter M.W. Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling Nat. Cell Biol. 14 2012 401 408 22388892 PMC3378643
  63. Youssef K.K. Van Keymeulen A. Lapouge G. Beck B. Michaux C. Achouri Y. Sotiropoulou P.A. Blanpain C. Identification of the cell lineage at the origin of basal cell carcinoma Nat. Cell Biol. 12 2010 299 305 20154679
  64. Youssef K.K. Lapouge G. Bouvrée K. Rorive S. Brohée S. Appelstein O. Larsimont J.C. Sukumaran V. Van de Sande B. Pucci D. Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation Nat. Cell Biol. 14 2012 1282 1294 23178882
  65. Zelger B. Zelger B.G. Burgdorf W.H. Dermatofibroma-a critical evaluation Int. J. Surg. Pathol. 12 2004 333 344 15494859

Cited by

Sorted by citations

Authors
Kretzschmar, K., Weber, C., Driskell, R. R., Calonje, E., & Watt, F. M.
Affiliations
  • Guy's Hospital (GB)
  • St Thomas' Hospital (GB)
Corresponding author
Watt, Fiona M.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2016-01
Volume
14
Issue
2
Pages
269-281
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2015.12.041
PMC
PMC4713864
OpenAlex
W2222290333
Cited by
72
References
3
Citations by year
2026: 9 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 9 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 9 · 2017: 6 · 2016: 1
FWCI
11.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Wellcome Trust (/Z/11/Z, 096540/Z/11/Z, 096540)
  • King's College Hospital NHS Foundation Trust
  • National Institute for Health and Care Research
  • King's College London
  • European Commission (EU-FP7)
  • Medical Research Council (MR/L022699/1, MC_PC_12009, G1100073)
Topics
  • Health Sciences › Medicine › Urology › Hair Growth and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Dermatology › Cancer and Skin Lesions
Keywords
β-catenin, Wnt signaling, epidermal stem cells, hair follicle regeneration, LGR6, Lrig1, Lgr5, pilomatrixoma, dermatofibroma, tumor heterogeneity, lineage reprogramming, sebaceous glands, dermal fibroblasts, extracellular matrix remodeling, immune cell infiltration, CD26, CD44, skin tumors
MeSH terms
Epidermal Cells, Animals, Cell Differentiation, Epidermis, Epithelial Cells, Signal Transduction, Cell Lineage, beta Catenin, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review